The Johns Hopkins Alzheimer's Disease Research Center (JHADRC) is an integrated program of investigators whose overarching goal is to improve understanding of the earliest phases of AD and to expand therapeutic approaches. The overall scientific focus of the JHADRC is on the earliest stages of AD and related disorders in humans and in model systems, through characterizing the earliest clinical and pathophysiological processes in humans, and by identifying cellular and molecular events that contribute to the abnormalities in model systems that capture aspects of the human disorders. We also focus efforts on improving care of patients in the symptomatic phases of disease. We have made substantial progress with these research goals during the current funding cycle (which is described below) and propose to continue and expand this work in the next funding cycle. The Center consists of 5 Cores: (1) the Administrative Core (Core A), (2) the Clinical Core (Core B), (3) the Data Management of Statistics Core (Core C), (4) the Neuropathology Core (Core D), and (5) the Outreach, Recruitment and Education Core (Core E). In this application we are proposing 3 new projects: (1) Project 1, to be led by Dr. Arnold Bakker (Assistant Professor of Psychiatry), will examine alterations in brain connectivity in MCI patients and subjects with subjective memory concerns vs. controls, and their relationship to AD CSF biomarkers. (2) Project 2, to be led by Dr. Philip Wong (Professor of Pathology and Neuroscience), will utilize a new mouse model of AD that closely mimics the human disease (by exhibiting both amyloidosis and tauopathy, and demonstrating neuronal loss) to test the hypothesis that amyloid induces tau aggregation to initiate synaptic dysfunction and promote loss of neurons. (3) Project 3, to be led by Dr. Richard Huganir (Professor and Chair of Neuroscience) will examine the impact of excitatory neurotransmitters and neuronal plasticity on synaptic alterations in the earliest phases of AD.